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Drug discovery relies on efficient identification of small-molecule leads and their interactions with macromolecular targets. However, understanding how chemotypes impact mechanistically important conformational states often remains secondary among high-throughput discovery methods. Here, we present a conformational discovery pipeline integrating time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS) and classic fragment screening applied to allosteric states of the mitochondrial import oxidoreductase apoptosis-inducing factor (AIF). By monitoring oxidized and X-ray-reduced AIF states, TR-HT-SAXS leverages structure and kinetics to generate a multidimensional screening dataset that identifies fragment chemotypes allosterically stimulating AIF dimerization. Fragment-induced dimerization rates, quantified with time-resolved SAXS similarity analysis (k VR ), capture structure-activity relationships (SAR) across the top-ranked 4-aminoquinoline chemotype. Crystallized AIF-aminoquinoline complexes validate TR-SAXS-guided SAR, supporting this conformational chemotype for optimization. AIF-aminoquinoline structures and mutational analysis reveal active site F482 as an underappreciated allosteric stabilizer of AIF dimerization. This conformational discovery pipeline illustrates TR-HT-SAXS as an effective technology for targeting chemical leads to important macromolecular states., (© 2024. The Author(s).)

Introduction: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in patients with PBC improve with OCA therapy., Methods: Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database., Results: In the RCT, the primary endpoint occurred in 28.6% of OCA (n = 168) and 28.9% of placebo patients (n = 166; intent-to-treat analysis hazard ratio [HR] = 1.01, 95% confidence interval = 0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting and as-treated analyses shifted the HR to favor OCA. In the EC (n = 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR = 0.39; 95% confidence interval = 0.22-0.69; P = 0.001). No new safety signals were identified in the RCT., Discussion: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the intent-to-treat estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Urinary tract infections (UTIs), including cystitis and pyelonephritis, are common. Each year, they account for more than 10 million outpatient visits and more than 3 million emergency department visits. Recurrent UTIs (defined as three in 1 year or two in 6 months) also are common, occurring in 20% to 30% of women. The annual incidence of UTIs is 12.1% among women and 3% among men. Cystitis symptoms include lower abdominal pain, dysuria, and urinary urgency or frequency. Escherichia coli is the most common pathogen. Cystitis often is diagnosed inappropriately when patients have asymptomatic bacteriuria (ie, positive urine culture result without symptoms). This can result in unnecessary antibiotic therapy. For uncomplicated acute cystitis in women, guidelines recommend nitrofurantoin for 5 days, trimethoprim-sulfamethoxazole for 3 days (if local drug-resistance rates are less than 20%), fosfomycin in a single dose, or pivmecillinam for 5 days. Effective prophylactic options for UTI include antibiotics and vaginal estrogen for postmenopausal women. Antibiotics are most effective but are associated with a risk of increased drug resistance. Patients with pyelonephritis present with costovertebral tenderness, fever, and urinary symptoms. Third-generation cephalosporins are preferred for management. Significant complications of pyelonephritis include sepsis or septic shock, obstructive pyelonephritis, emphysematous pyelonephritis, perinephric abscess, and kidney transplant rejection. For pregnant patients with pyelonephritis, hospitalization and intravenous antibiotics are indicated.

Background and Aims: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar's antipruritic effects and IL-31 and bile acid levels in patients with PBC., Approach and Results: IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS ( r = 0.54, p < 0.0001), and total ( r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p = 0.0003) and 10 mg (-52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids ( r = 0.63, p < 0.0001) in the seladelpar 10 mg group., Conclusions: Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar's antipruritic effects., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hematologic emergencies are bleeding or clotting disorders that are hereditary or acquired and must be treated emergently to avoid significant morbidity or mortality. Patients experiencing a hematologic emergency may present with spontaneous bleeding, jaundice, petechiae, or purpura. Initial diagnostic testing should include a complete blood count. Patients who have bleeding associated with a hereditary disorder should receive clotting factor replacement before diagnostic testing. Acute chest syndrome is an uncommon but serious complication of sickle cell disease. Hemolysis caused by autoimmune disorders or iatrogenic errors from blood product transfusions has a distinct clinical presentation and requires immediate action. Severe thrombocytopenia presenting as immune or thrombotic thrombocytopenic purpura should be differentiated and treated appropriately. Disseminated intravascular coagulation and trauma coagulopathy are sometimes confused with each other, but both can cause serious injury and require unique treatments. Primary care physicians should promptly recognize patients who require emergent referral to a hematologic specialist.

Interparental conflict is known to negatively impact child well-being, including behavioral and physiological well-being. Children's empathy - that is, vicariously experiencing others' emotions - may increase children's sensitivity to and the biological repercussions of interparental conflict. Although empathy represents a valued trait and is an important part of socioemotional development, its influence on children's physical health is unknown. This study examined whether empathy moderates the association between perceived interparental conflict and both child systemic inflammation and parent-rated overall child health in a sample of children between the ages of seven to nine. Children and their parents participating in the long-term evaluation of the Family Foundations program, a randomized trial of a perinatal preventative intervention, provided data approximately eight years following enrollment into the program. We collected peripheral blood samples via dried blood spots, anthropometric measurements, and child and parent psychosocial questionnaires. Results indicated significant positive main effects of child empathy on both C-reactive protein (CRP; B = 0.26, SE = 0.11, p =.026) and Interleukin-6 (IL-6; B = 0.20, SE = 0.10, p =.045) levels. Further, child affective empathy moderated the associations between perceived interparental conflict and both CRP (B = 0.39, SE = 0.19, p =.050) and parent-reported child health (B = 0.30, SE = 0.13, p =.021), such that greater empathy strengthened the negative associations between interparental conflict and child health. Overall, findings suggests that there may be a biological cost of being more empathic in high-conflict environments and highlight the need for tools to help more empathic children appropriately manage vicarious emotions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mark Feinberg created the Family Foundations program and is the owner of a private company, Family Gold, which disseminates the Family Foundations program. His financial interest has been reviewed by the Institutional Review Board and the Conflict of Interest Committee at The Pennsylvania State University. The other authors declare no conflicts of interest. Research presented here was supported via funding from the National Heart, Lung, and Blood Institute (R01 HL137809 (Schreier)) and Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01s HD058529 and HD084476 (Feinberg); T32HD101390 (Ganguli))., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Malakoplakia is a rare disease that manifests as a histiocytic inflammatory process and most often occurs in the urinary bladder. It is caused by an impaired capacity of histiocytes to kill and digest bacteria. The typical histopathologic findings are sheets of histiocytes with granular eosinophilic cytoplasm and characteristic Michaelis-Gutmann bodies, spherical bodies with a targetoid appearance. Malakoplakia is even rarer in the gynecologic tract, and our literature search found only 21 published patients of malakoplakia involving the endometrium. Here we report a 60-year-old female patient who presented with recurrent pelvic infections and postmenopausal bleeding, which raised concern for an endometrial malignancy. Hysterectomy with salpingo-oophorectomy revealed malakoplakia involving the endometrium and also the right ovary. Michaelis-Gutmann bodies were visible on the intraoperative frozen section that was performed to rule out an endometrial malignancy. We summarize the clinicopathologic findings of the published patients of endometrial malakoplakia., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The Recipe 4 Success preventive intervention targeted multiple factors critical to the health and well-being of toddlers living in poverty. This randomized controlled trial, which was embedded within Early Head Start home visits for 12 weeks, included 242 racially and ethnically diverse families (51% girls; toddler mean age = 2.58 years; data collected 2016-2019). Compared to parents in usual practice home visits, parents in Recipe 4 Success displayed greater sensitive scaffolding of toddlers' learning and more responsive food parenting practices (Cohen's d = .21-.30). Toddlers in Recipe 4 Success exhibited greater self-regulation and had healthier eating habits (Cohen's d = |.16-.35|). Results highlight the value of Recipe 4 Success in promoting parent and toddler behavior change that could have life-long benefits., (© 2023 The Authors. Child Development published by Wiley Periodicals LLC on behalf of Society for Research in Child Development.)

Background: Across several sites in the United States, we examined whether kindergarten conduct problems among mostly population-representative samples of children were associated with increased criminal and related (criminal + lost offender productivity + victim; described as criminal + victim hereafter) costs across adolescence and adulthood, as well as government and medical services costs in adulthood., Methods: Participants (N = 1,339) were from two multisite longitudinal studies: Fast Track (n = 754) and the Child Development Project (n = 585). Parents and teachers reported on kindergarten conduct problems, administrative and national database records yielded indexes of criminal offending, and participants self-reported their government and medical service use. Outcomes were assigned costs, and significant associations were adjusted for inflation to determine USD 2020 costs., Results: A 1SD increase in kindergarten conduct problems was associated with a $21,934 increase in adolescent criminal + victim costs, a $63,998 increase in adult criminal + victim costs, a $12,753 increase in medical services costs, and a $146,279 increase in total costs. In the male sample, a 1SD increase in kindergarten conduct problems was associated with a $28,530 increase in adolescent criminal + victim costs, a $58,872 increase in adult criminal + victim costs, and a $144,140 increase in total costs. In the female sample, a 1SD increase in kindergarten conduct problems was associated with a $15,481 increase in adolescent criminal + victim costs, a $62,916 increase in adult criminal + victim costs, a $24,105 increase in medical services costs, and a $144,823 increase in total costs., Conclusions: This investigation provides evidence of the long-term costs associated with early-starting conduct problems, which is important information that can be used by policymakers to support research and programs investing in a strong start for children., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)